Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.

Abstract

Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.

• Authors: Badr Jismy, Abdelkarim El Qami, Anja Pišlar, Rok Frlan, Janko Kos, Stanislav Gobec, Damijan Knez, Mohamed Abarbri
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 209 Pg. 112911 (Jan 01 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33071056 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• 1H-indazol-3-amine
• Antiparkinson Agents
• Bromides
• Coordination Complexes
• Indazoles
• Metals
• Monoamine Oxidase Inhibitors
• Neuroprotective Agents
• Small Molecule Libraries
• Monoamine Oxidase
• Tyramine

Topics

• Antiparkinson Agents (chemical synthesis, chemistry, pharmacology)
• Bromides (chemistry)
• Coordination Complexes (chemistry)
• Humans
• Indazoles (chemical synthesis, chemistry, pharmacokinetics)
• Metals (chemistry)
• Molecular Docking Simulation
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (chemical synthesis, pharmacokinetics)
• Neuroblastoma (drug therapy)
• Neuroprotective Agents (chemical synthesis, pharmacokinetics)
• Protein Binding
• Small Molecule Libraries (chemical synthesis, pharmacokinetics)
• Structure-Activity Relationship
• Tyramine (chemistry)